Mantle cell lymphoma (MCL), characterized by a t(11;14) translocation that results in up-regulation of cyclin D1, is incurable with standard chemotherapy. Several new drugs are currently undergoing early clinical testing in MCL. Proteasome inhibition interferes with protein homeostasis and induces apoptosis. Up to 50% of patients with relapsed mantle cell lymphoma (MCL) respond to bortezomib. To investigate the connection between proteasome inhibition, cellular response, and clinical efficacy we used gene expression profiling. In 10 MCL cell lines exposed to bortezomib in vitro we found induction of endoplasmic reticulum and oxidative stress response pathways. Purified tumor cells from five patients with leukemic MCL undergoing treatment with bortezomib showed primarily activation of oxidative stress response pathways leading to upregulation of ATF4 and NRF2 that induce antioxidant response genes. Surprisingly, activation of this homeostatic program was significantly stronger in sensitive cells. Consistent with its pro-apoptotic function we found up-regulation of NOXA only in responding patients. In resistant cells gene expression changes in response to bortezomib were limited and upregulation of Noxa was absent. Interestingly, before treatment bortezomib resistant cells displayed a relatively higher expression of the NRF2 gene expression signature than sensitive cells. This may increase the cellular anti-oxidant capacity and contribute to bortezomib resistance. In summary, NRF2 is a critical integrator of bortezomib induced cellular stress, may serve as a biomarker for response, and become a target for combination therapy. While bortezomib induces remissions in 30-50% of patients with relapsed MCL more than half of patients tumors are resistant to bortezomib. To investigate the molecular mechanisms of resistance we generated a model of bortezomib-adapted subclones of MCL cell lines JEKO and HBL2 that were 40-80 fold less sensitive to bortezomib than the parental cells. Acquisition of bortezomib resistance was gradual and reversible. Bortezomib-adapted subclones showed increased proteasome activity and tolerated lower proteasome capacity than the parental lines. Using gene expression profiling we discovered that bortezomib resistance was associated with plasmacytic differentiation including upregulation of IRF4 and CD38, and expression of CD138. In contrast to plasma cells, plasmacytic MCL cells did not increase immunoglobulin secretion. Intrinsically bortezomib resistant MCL cell lines and primary tumor cells from MCL patients with inferior clinical response to bortezomib also expressed plasmacytic features. Knock-down of IRF4 was toxic for the subset of MCL with plasmacytic differentiation, but only slightly sensitized cells to bortezomib. We conclude that plasmacytic differentiation in the absence of an increased secretory load can enable cells to withstand the stress of proteasome inhibition. Expression of CD38 and IRF4 could serve as markers of bortezomib resistance in MCL. The clinical success of bortezomib has indicated that protein homeostasis in the endoplasmic reticulum is a valid therapeutic target for cancer treatment. We found that the ERAD inhibitor Eeyarestatin I (EerI) induces an ER stress response similar to bortezomib and can synergize with bortezomib to induce apoptosis in hematologic cancer cells. We identifed a nitrofuran-containing (NFC) domain in EerI as the functional group responsible for its anti-cancer activity and showed that the cytotoxic activities of EerI are caused by the binding of the NFC-domain to p97 ATPase, an essential component of the ERAD machinery. An aromatic domain in EerI, although not required for p97 interaction, can recruit EerI to the ER membrane and thus improve its target specificity and tumor selectivity. These results reveal a bifunctional agent that induces cell death in hematologic cancer cells by preferentially inhibiting membrane-bound p97. Testing in the NCI60 panel revealed that EerI is cytotoxic to a large number of cancer cell lines with a pattern of activity similar to bortezomib. Unexpectedly, EerI was also cytotoxic to bortezomib resistant MCL cells suggesting that inhibition of ER-associated p97 may be a strategy to overcome bortezomib resistance. This work has led to two patent applications. To identify novel therapeutic targets, we contributed to an analysis of genome-wide methylation patterns in MCL using the HELP (Hpa II tiny fragment Enrichment by Ligation mediated PCR) assay. Significant aberrancy in promoter methylation patterns as compared to normal B-cells could be demonstrated. Four hypermethylated genes CDKN2B, MLF-1, PCDH8, HOXD8 and four hypomethylated genes CD37, HDAC1, NOTCH1 and CDK5 were identified. Immunohistochemical analysis of an independent cohort of MCL patient samples confirmed CD37 surface expression in 93% of patients and a small modular immunopharmaceutical resulted in significant cell death validating this target. Treatment of MCL cell lines with the DNA methyltransferase inhibitor decitabine resulted in reversal of aberrant hypermethylation and synergized with the HDAC inhibitor SAHA in induction of the hypermethylated genes and anti-MCL cytotoxicity. These data suggest that differentially methylated genes can be targeted for therapeutic benefit in MCL.